Aggregatibacter actinomycetemcomitans (Aa) has been implicated as the causative agent of localized aggressive periodontitis (LAP), a severe form of periodontal disease that can lead to premature tooth loss in adolescents. This rapid form of periodontal disease affects more than 70,000 adolescents annually in the US alone. African-Americans have a 15-fold greater incidence of the disease than Caucasian-Americans making LAP a disproportionate burden on minorities and the poor. We recently have identified two new polymorphisms of the lactoferrin (Lf) gene that are involved in LAP. One polymorphic alteration occurs at the codon 11 (alanine/threonine) and the other is localized in the LPS binding region at codon 29 (arginine/lysine). Preliminary data suggests that genetic polymorphisms of Lf may play a significant role in determining an individual's susceptibility to the LAP. The research outlined in this revised proposal will test this hypothesis using a mouse model and focusing on the functional characterization of genetic polymorphisms of Lf. The specific aims of the research are to 1) Generate bigenic Lf-variants/Lf-knockout mice;2) Determine the anti-bacterial and anti-inflammatory activities against Aa colonization and infection in bigenic Lf-variants/Lf-/- and Lf-/- mice. The results of the proposed research will contribute to our understanding of the functional role of Lf polymorphisms in LAP and provide new approaches to prevention of this disease based on functional differences in single nucleotide polymorphisms (SNPs) in the Lf gene.